The proposed K23 career development and research plans will prepare EdmondP. Wickham 111, M.D., for a productive career as an independent clinicalinvestigator focusing on the role of traditional andnon-traditional cardiovascular risk factors in the vascular dysfunction frequently present in overweight and obese adolescents. The candidate seeks to combine his unique training in Pediatrics, Internal Medicine, and Endocrinology to examine the relationships among adiponectin multimers, circulating progenitor cell number and function, and endothelial function in adolescents. The candidate will complete formal didactic training in study design, biostatistics, and publichealth resulting in a Masters of Public Health degree. He will integrate this classroom training with the completion of a multi-disciplinary research protocol under the guidance of a diverse team of mentors, each with exceptional research and training records. The proposed studies will test the hypothesis that in adolescents, adiponectin (with particular emphasis on the high molecularweight [HMW]isoform) contributes to endothelial dysfunction,in part through its effects on circulating progenitor cell (CPC)number and function. To test this hypothesis, the candidate will measure traditional cardiovascular risk factors (blood pressure, waist circumference, lipids,glucose), insulin resistance (using glucose and insulinvalues during an oral glucose tolerance test), inflammatory cytokines,adiponectin multimers, CPC number (CD34+ cells determined by flow cytometry), and flow-mediateddilation (FMD) of the brachial artery in 30 normal-weight, 30 overweight, and 100 obese adolescents ages 11-18. Baseline measures will be repeated in 60 of the obese adolescents after 12-weeks of participation in a family-based, structured weight management program. Additionally, in vitro CPC studies (quantificationof colony forming units [CFU- Hill] and CPC incorporation during a tubule formation assay) will be performed on cells isolated from 30 obese adolescents (ages 14-18) with the metabolic syndrome (MetS) and 30 normal-weight children. Finally, in a subset of 20 adolescents (10 obese-MetS, 10 normal-weight), a second tubule formation assay will beperformed in the presence of human recombinant adiponectin to determine the effects of adiponectin on CPCfunction. RELEVANCE (See instructions): Obese adolescents are at increased risk of developing significant health problems including diabetes mellitus, elevated cholesterol, and elevated blood pressure; each of which is associated with an increased risk of cardiovascular disease. Adiponectin, a hormone released by fat cells, may play an important role in the early blood vessel changes that ultimately lead to heart disease.